Purpose: The purpose of the present study is to determine the safety and tolerability and potential clinical efficacy of subcutaneous doses of recombinant human IL-10 (rHuIL-10) in patients with rheumatoid arthritis (RA). RA is a chronic inflammatory disease of unknown etiology. It is characterized by synovial inflammation with frequent progression to articular cartilage and bone destruction. The synovial inflammatory response in RA consists predominately of T lymphocytes, mostly T helper cells (Th), with fewer numbers of macrophages and B lymphocytes. RA is widely believed to be a Th1-mediated disease, although the data to support this hypothesis is circumstantial. For example, Th1 cells are associated with cellular immune responses, which seems to fit with the characteristics of rheumatoid joint inflammation, and T cell clones isolated from synovial tissue of RA patients most often secrete Th1 cytokines (such as interferon). IL-10, a cytokine produced by Th2 cells and macrophages, has primarily immunosuppressive and anti-inflammatory properties. The inhibitory effects of IL-10 have been observed in animal models of arthritis where treatment with this cytokine can ameliorate joint inflammation. Methods: The study is a phase II, multicenter, double-blind, placebo-controlled, clinical trial of daily (4 5g/d, 8 5g/d, or placebo) or three times week (8 5g/d, 20 5g/d or placebo) subcutaneous rHuIL-10 therapy. The dosing period is twelve weeks for the randomized phase and an additional 12 weeks for the extension study. The study was amended to include an open label portion with a total of 80 weeks of treatment. The main outcomes are the frequency and severity of adverse effects and the American College of Rheumatology Core Disease Measures. Results: The study is ongoing, but enrollment has been completed. A total of 18 patients were screened with 10 completing the initial portion of the protocol. 8 patients moved to the extension, with 6 continuing into the open label portion of the study. Currently, 3 patients remain active in the open label portion of the protocol with 2 patients sheduled for early termination and final follow- up visits during the month or December, 1998. Our site enrolled 7 Caucasian females, 2 Caucasian males, and 1 Afro-American male. There have been 8 serious adverse events involving patients who were hospitalized and with problems that were possibly related to the study drug. They were as follows: 1) Diverticulitis and urinary tract infection; 2) Supraventricular tachycardia; 3) Breast Cancer; 4) Allergic interstitial nephritis; 5) Demyelinating disease with left sided numbness 6) RA flare with pneumonia; 7) Death following cardio-vascular collapse; 8) Nausea, vomiting and diarrhea resulting in dehydration , electrolyte imbalance and hypotension. The results of the phase I study showed that the study drug was well-tolerated and did not cause any serious adverse reactions. Platelet counts dropped significantly in several patients receiving the two highest doses of IL-10, with platelet counts in 2 cases dropping below 100,000/mm3. There were no bleeding complications, and the thrombocytopenia was quickly reversible upon stopping the study. No responders were noted in the two lowest dosage cohorts, but in the 5 5g/d dosage cohort, 3 of 8 patients were classified as responders. These preliminary results suggested that IL-10 therapy may offer some clinical benefits to patients with RA without causing major toxicity. Significance: Insights into whether RA is a Th1-driven response in RA may be obtained by examining the treatment and biological effects of cytokines that downregulate Th1 responses. The results of the phase I study are preliminary and do not yet provide sufficient evidence to prove or refute the Th1 hypothesis. Furthermore, the results of this small trial and future studies may be difficult to interpret because of the knowledge that cytokines are pleiotropic in their actions and may exhibit unique synergistic effects in the company of other cytokines. For example, IL-10 inhibits cytokine production by Th1 cells, inhibition of antigen presentation and cytokine production by macrophages and monocytes, and enhances of B-cell proliferation and antibody secretion. In addition, redundant cytokine and other inflammatory pathways exist in vivo that may compensate for the lack or excess of a particular cytokine. Future plans: A phase I study of IL-10 and methotrexate is ongoing and a larger phase III study of IL-10 is planned for 1999. The projected endpoint for the open label portion of the phase II trial is February/March, 2000.